Periodontitis and Depressive Disorders: The Effects of Antidepressant Drugs on the Periodontium in Clinical and Preclinical Models: A Narrative Review

Background/Objectives: Several psychological conditions, including stress and depression, can adversely affect oral health; in fact, antidepressants, commonly used to treat depressive disorders, may have conflicting effects on the periodontal status of individuals. The aim of this review was to determine the effects of antidepressants on the periodontium. Methods: A literature search was conducted using electronic databases, Pubmed/MEDLINE, Cochrane Library, focusing on the use of antidepressants and their effects on periodontal health in animals or humans. Results: Seventeen articles have been included with the use of amitriptyline (two studies), desipramine (one study), imipramine (two studies), desvenlafaxine (one study), fluoxetine (six studies), venlafaxine (three studies) and tianeptine (two studies). One study evaluated several categories of antidepressants, such as selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), tricyclic, atypical and monoamine oxidase inhibitors (MAO). Most trials showed improvements in periodontal health, especially with fluoxetine, but also with imipramine, desipramine, desvenlafaxine and tianeptine; on the contrary, worsening of clinical periodontal indices and increased loss of alveolar bone were reported with venlafaxine. Conclusions: This review suggests that in the presence of comorbidity between periodontitis and depression, pharmacological treatment with SNRIs, SSRIs and mixed antidepressants is associated with improvement in periodontal parameters, except for venlafaxine. Healthcare professionals (especially oral and mental health professionals) should investigate proper adherence to medication therapy in patients with a history of periodontitis and depression. Further clinical trials are needed to confirm these results.


Introduction
Periodontal disease is a problem that affects the worldwide population: global cases of severe periodontitis were reported to be approximately 1.1 billion in 2019, an increase of 99% from 1990 to 2019, and this is attributable to population growth and increased ageing [1].It affects almost 40% of the world's population [2].
Periodontitis is a chronic inflammatory disease of multifactorial etiology associated with dysbiotic plaque biofilms that progressively weaken and destroy the oral tissues supporting the tooth within the alveolar bone [3][4][5].Periodontitis can be successfully treated with various therapies, such as mechanical or manual instrumentation, which aim that changed daily (two stressors/day)), showed significantly greater alveolar bone loss at the level of the bifurcation than the non-depressed groups with induced periodontitis.Fusobacterium nucleatum has been found in the frontal cortex of mice with periodontally induced depression [34].
Starting from preclinical studies on animal models, other studies have tried to investigate the associations between these pathologies in subjects with periodontitis compared to healthy individuals.A study comparing approximately 50,000 healthy subjects vs. 12,000 with periodontitis demonstrated that subjects with periodontitis were more likely to develop depression within 10 years of follow-up, indicating periodontitis as a risk factor for depression later, regardless of other associated comorbidities such as sex and age [35]; not only could periodontal disease be a risk factor for affective disorders: depression could also be a risk factor for periodontal disease, indicating a two-way link [36].
A recent meta-analysis, published in the Journal of Clinical Periodontology in 2021, indicated the plausibility of a bidirectional depression-periodontitis association, dividing the possible mechanisms involved into three aspects: behavioural, biological/physiological and bacteriological aspects [37].
Depressed subjects tend to engage in riskier behaviours, which can worsen oral health and predispose them to periodontitis [33][34][35][36][37][38].Periodontitis is one of the main causes of edentulism in the population, which can compromise the contour and aesthetics of the face [39].Periodontal disease significantly affects the patient's quality of life and masticatory function, as well as worsens self-confidence: all of these factors can predispose periodontal patients to a significant worsening of mood, with an increased risk of depression [40][41][42][43][44][45].
Individuals with depression report increased levels of certain inflammatory production factors, including interleukin-6 (IL-6), tumour necrosis factor (TNF)-alpha, interleukink-10 (IL-10), as well as several soluble receptors and interleukin antagonists and cytokines, such as the soluble IL-2 receptor, IL-13 and IL-1 receptor antagonist [46][47][48].From here, the hypothesis of "inflammatory depression" was born, a real subtype of depression, which identifies mechanisms that act as catalysts/amplifiers of responses: bad eating habits, stress and sedentary lifestyle [49].In contrast, among the possible protective factors against the development of depression, probiotics have been proposed and studied as adjuvants in the non-surgical treatment of periodontitis [49][50][51].
Therefore, individuals with depression and periodontitis appear to share an alteration in the production of various pro-inflammatory factors (IL-1, IL-6, TNF-α), which, on the one hand, increases the individual's systemic inflammatory load [52] and, on the other hand, increases neuroinflammation [53,54].Cortisol-related stress is also associated with periodontitis [55].In fact, cortisol could be differentiated into different forms of periodontitis: subjects with aggressive periodontitis had higher cortisol levels than subjects with chronic periodontitis [56].Cortisol, resulting from the incorrect functioning of the hypothalamic-pituitary-adrenal (HPA) axis, induces endocrine and cerebral changes, increasing vulnerability to the development of depressive pathologies.Therefore, by increasing its serum production, it can cause the reduction in cellular trophism of neurons and the inhibition of neurogenesis mechanism [57], all of which seem to significantly predispose subjects to mental pathology [58].Similarly, "inflammatory depression" induces a functional alteration of the HPA axis with increased secretion of pro-inflammatory cytokines such as IL-6 and TNF-α; the latter are in turn associated with the development of periodontitis [37,47,52,54,59].Therefore, depression and periodontitis share a potential bidirectionality in the etiology and maintenance of pathology [60].
Virulence factors of some periodontal disease pathogens can overcome the bloodbrain barrier and negatively influence the physiology of the brain via glial cells, which are mediators of various neural signals [61,62].
Antidepressants are widely used in the population, particularly in the periodontal population: subjects with periodontitis are more likely to take antidepressant drugs when compared to healthy patients [63].Although the various anti-inflammatory functions of these drugs are well known in the literature, acting also at the level of systemic inflammation and enhancing the individual's immune response [64][65][66], the literature seems to be divided on their effects at the periodontal level, except for one study where it was found that the use of antidepressants could protect against periodontal disease, noting a lower loss of clinical attachment; the explanation of this effect is unclear [67].However, other studies in the literature mention some factors at the oral level, such as bacterial infections and accumulation of bacterial biofilm, which favour the development of periodontal disease [68,69].
Therefore, the aim of this study was to determine the periodontal effects of the antidepressant drugs most commonly used to treat different forms of depression, as there are few studies focused on researching the periodontal effects of these drugs.

Hypothesis
Are there any periodontal effects of antidepressant drugs?What are the effects of antidepressants at the periodontal level?

Eligibility Criteria
The following inclusion criteria guided the analysis of the studies: Study type.Clinical and preclinical studies in patients or animals, i.e., randomised, blind/double-blind clinical trials, case-control, cross-sectional, cohort and observational studies and reviews; Type of participants.Patients or animals with experimentally induced periodontitis and/or depression; Type of interventions.Pharmacological treatments for all clinical and subclinical forms of depression.Changes in parameters of periodontal inflammation and diagnosis of periodontitis; changes in laboratory and genetic study variables (serum biomarker titration and gene expression tests); Type of results.Determination of positive and negative effects of antidepressants at the periodontal level.
Only studies that met all the inclusion criteria were included.However, the following exclusion criteria were considered: articles published before 2005, in vitro studies, studies evaluating inflammatory parameters in oral pathologies other than periodontal disease (because the focus of this review is periodontal disease), studies in which the comparator molecule is used to treat pathologies associated with depression, such as anxiety disorders (benzodiazepines and beta-blockers), and articles on peri-implantitis and implant loss.

Search Strategy
The population, intervention, comparison, outcome (PICO) model was used to perform this narrative review through research of studies identified in electronic databases, Pubmed/MEDLINE and the Cochrane Library.Initially, all study abstracts were taken into consideration, and all studies that met the inclusion criteria and evaluated changes in periodontal parameters in clinical or pre-clinical models using antidepressant drugs were reviewed and analysed.
We performed the search using the following keywords: ''antidepressant and periodontitis"; "antidepressant and periodontal disease"; "antidepressant and periodontal health"; "antidepressant and periodontal status"; and "antidepressant and periodontal inflammation".

Screening and Selection of Articles
The electronic search yielded 130 results, which were examined to determine whether the inclusion and exclusion criteria were met; all duplicates emerging from the different searches were removed (one authors).
In the first phase, the results (abstracts) were filtered based on the use of pharmacological treatments for all clinical and subclinical forms of depression; all those that did not evaluate changes in the parameters of periodontal inflammation or met the eligibility criteria were discarded.Authors (all) continued with the reading of the articles included.
After reading the selected articles, all those that had not reported the results required by the criteria for inclusion of this review, or which evaluated other oral epidemiological factors and indices other than periodontal health were removed (three authors).

Risk of Bias and Results
One author was involved in the analysis of the articles included and evaluated the results according to the PICO model.Two other authors were commissioned to evaluate the quality of the included studies, following the full reading of the articles [69].

Results
The main results of these studies are shown in Table 1.[68] Case-control study conducted on humans

Absence of periodontitis/diagnosis of depression at t0
Group 1: Subjects identified by a psychiatrist as having a mental illness (control) after presenting to the psychiatry outpatient department (OPD); Group 2: patients who are taking venlafaxine; Group 3: patients who are taking fluoxetine.

CAL, PPD, CI, DI
Antidepressants can be a risk factor for periodontal health, with an increase in periodontal parameters, as these drugs can put periodontal tissues at risk.The periodontitis group and fluoxetine demonstrated less alveolar bone loss at histometric evaluation compared to the group with induced periodontitis alone and placebo.Furthermore, in the fluoxetine group there was a reduced inflammatory expression of IL-1β (interleukin 1-beta) and COX-2 (cyclooxygenase-2).The electronic search yielded 130 results, and 17 articles met the eligibility criteria and were included in this narrative review.
The antidepressant drug that seems to make periodontal health worse is venlafaxine (in all studies that have analyzed its effects), with an increase in clinical indices such as gingival index, periodontal pocket depth, clinical attachment loss (p < 0.05) [67,68] and inflammation and bone loss (p < 0.001) [76].
For the two amitriptyline studies, there are two different results: in one study (RCT) where amitriptyline gel or mouthwash was used, there was an improvement in periodontal health and a reduction in the epidemiological indices (p < 0.001) analysed (probing depth, attachment level, tooth mobility, plaque index, gingival index and bleeding on probing) [70], while in the second study (in rats), when amitriptyline was administered as a tablet for 4 weeks, a deterioration in periodontal health was noticed, with reduced bone mineral density [71].Discordant results also emerge from the studies that analysed the effects of fluoxetine: it reduced bone loss and inflammatory parameters, with noted improvements in gingival index, sulcus bleeding index, bleeding on probing, probing depth, attachment level [77][78][79]; however, other studies have shown a worsening of the epidemiological indices related to periodontal disease [67,68] and a decrease in periodontal cells, although no structural periodontal changes in the analysis were noted [80].
For imipramine, desipramine, desvenlafaxine and tianeptine, there were improvements in periodontal status in all studies.
Table 2 shows a summary of the antidepressant used and its effect on the periodontium.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, ou and outcome recording were carried out to assess the bias risk of this review.to the variable taken into consideration, a green symbol was assigned information was complete and accurate; a yellow symbol was alloca information was missing; and a red symbol was assigned where the informat meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, ou and outcome recording were carried out to assess the bias risk of this review.to the variable taken into consideration, a green symbol was assigned information was complete and accurate; a yellow symbol was alloca information was missing; and a red symbol was assigned where the informat meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, rand and outcome recording were carried o to the variable taken into considera information was complete and acc information was missing; and a red sy meet the requirements.This review ha Table 3 shows the risk of bias in th

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, rand and outcome recording were carried o to the variable taken into considera information was complete and acc information was missing; and a red sy meet the requirements.This review ha Table 3 shows the risk of bias in th

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, ou and outcome recording were carried out to assess the bias risk of this review.to the variable taken into consideration, a green symbol was assigned information was complete and accurate; a yellow symbol was alloca information was missing; and a red symbol was assigned where the informat meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

sk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data d outcome recording were carried out to assess the bias risk of this review.According the variable taken into consideration, a green symbol was assigned where the formation was complete and accurate; a yellow symbol was allocated where formation was missing; and a red symbol was assigned where the information did not eet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, ou and outcome recording were carried out to assess the bias risk of this review.to the variable taken into consideration, a green symbol was assigned information was complete and accurate; a yellow symbol was alloca information was missing; and a red symbol was assigned where the informat meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, ou and outcome recording were carried out to assess the bias risk of this review.to the variable taken into consideration, a green symbol was assigned information was complete and accurate; a yellow symbol was alloca information was missing; and a red symbol was assigned where the informat meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

sk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data d outcome recording were carried out to assess the bias risk of this review.According the variable taken into consideration, a green symbol was assigned where the formation was complete and accurate; a yellow symbol was allocated where formation was missing; and a red symbol was assigned where the information did not eet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, ou and outcome recording were carried out to assess the bias risk of this review.to the variable taken into consideration, a green symbol was assigned information was complete and accurate; a yellow symbol was alloca information was missing; and a red symbol was assigned where the informat meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, rand and outcome recording were carried o to the variable taken into considera information was complete and acc information was missing; and a red sy meet the requirements.This review ha Table 3 shows the risk of bias in th

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, ou and outcome recording were carried out to assess the bias risk of this review.to the variable taken into consideration, a green symbol was assigned information was complete and accurate; a yellow symbol was alloca information was missing; and a red symbol was assigned where the informat meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, ou and outcome recording were carried out to assess the bias risk of this review.to the variable taken into consideration, a green symbol was assigned information was complete and accurate; a yellow symbol was alloca information was missing; and a red symbol was assigned where the informat meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.Table 3 shows the risk of bias in the main articles examined.to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.Table 3 shows the risk of bias in the main articles examined.to the variable taken into consideration, a green sym information was complete and accurate; a yellow s information was missing; and a red symbol was assigned meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles exam to the variable taken into considera information was complete and acc information was missing; and a red sy meet the requirements.This review ha Table 3 shows the risk of bias in th The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.

Adequate
Table 3 shows the risk of bias in the main articles examined.The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.

Adequate
Table 3 shows the risk of bias in the main articles examined.The evaluation of blinding, rand and outcome recording were carried o to the variable taken into considera information was complete and acc information was missing; and a red sy meet the requirements.This review ha Table 3 shows the risk of bias in th cluded f blinding, randomisation, allocation concealment, outcome data g were carried out to assess the bias risk of this review.According into consideration, a green symbol was assigned where the plete and accurate; a yellow symbol was allocated where ing; and a red symbol was assigned where the information did not

Adequate
. This review has low risk of bias.
risk of bias in the main articles examined.

sk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data d outcome recording were carried out to assess the bias risk of this review.According the variable taken into consideration, a green symbol was assigned where the formation was complete and accurate; a yellow symbol was allocated where formation was missing; and a red symbol was assigned where the information did not eet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, ou and outcome recording were carried out to assess the bias risk of this review.
to the variable taken into consideration, a green symbol was assigned information was complete and accurate; a yellow symbol was alloca information missing; and a red symbol was assigned where the informat meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, ou and outcome recording were carried out to assess the bias risk of this review.
to the variable taken into consideration, a green symbol was assigned information was complete and accurate; a yellow symbol was alloca information was missing; and a red symbol was assigned where the informat meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

sk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data d outcome recording were carried out to assess the bias risk of this review.According the variable taken into consideration, a green symbol was assigned where the formation was complete and accurate; a yellow symbol was allocated where formation was missing; and a red symbol was assigned where the information did not eet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, ou and outcome recording were carried out to assess the bias risk of this review.
to the variable taken into consideration, a green symbol was assigned information was complete and accurate; a yellow symbol was alloca information was missing; and a red symbol was assigned where the informat meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

sk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data d outcome recording were carried out to assess the bias risk of this review.According the variable taken into consideration, a green symbol was assigned where the formation was complete and accurate; a yellow symbol was allocated where formation was missing; and a red symbol was assigned where the information did not eet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, ou and outcome recording were carried out to assess the bias risk of this review.
to the variable taken into consideration, a green symbol was assigned information was complete and accurate; a yellow symbol was alloca information was missing; and a red symbol was assigned where the informat meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

sk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data d outcome recording were carried out to assess the bias risk of this review.According the variable taken into consideration, a green symbol was assigned where the formation was complete and accurate; a yellow symbol was allocated where formation was missing; and a red symbol was assigned where the information did not eet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, ou and outcome recording were carried out to assess the bias risk of this review.to the variable taken into consideration, a green symbol was assigned information was complete and accurate; a yellow symbol was alloca information was missing; and a red symbol was assigned where the informat meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, rand and outcome recording were carried o to the variable taken into considera information was complete and acc information was missing; and a red sy meet the requirements.This review ha Table 3 shows the risk of bias in th

sk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data d outcome recording were carried out to assess the bias risk of this review.According the variable taken into consideration, a green symbol was assigned where the formation was complete and accurate; a yellow symbol was allocated where formation was missing; and a red symbol was assigned where the information did not eet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, ou and outcome recording were carried out to assess the bias risk of this review.to the variable taken into consideration, a green symbol was assigned information was complete and accurate; a yellow symbol was alloca information was missing; and a red symbol was assigned where the informat meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, rand and outcome recording were carried o to the variable taken into considera information was complete and acc information was missing; and a red sy meet the requirements.This review ha Table 3 shows the risk of bias in th

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, ou and outcome recording were carried out to assess the bias risk of this review.to the variable taken into consideration, a green symbol was assigned information was complete and accurate; a yellow symbol was alloca information was missing; and a red symbol was assigned where the informat meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, randomisation, allocation concealment, outcome data and outcome recording were carried out to assess the bias risk of this review.According to the variable taken into consideration, a green symbol was assigned where the information was complete and accurate; a yellow symbol was allocated where information was missing; and a red symbol was assigned where the information did not meet the requirements.This review has low risk of bias.
Table 3 shows the risk of bias in the main articles examined.

Risk of Bias of Studies Included
The evaluation of blinding, rand and outcome recording were carried o to the variable taken into considera information was complete and acc information was missing; and a red sy meet the requirements.This review ha Table 3 shows the risk of bias in th

Discussion
Recent studies [32,84] have suggested a strong link between oral health and systemic diseases, one of which is mental health with depression.
The link between periodontal disease and depression can be explained by behavioural, biological and bacteriological factors.
Periodontitis is an inflammatory disease, and inflammatory factors such as IL-1, IL-6 and TNF-α are directly associated with periodontitis [85].Some of these biomarkers appear to play a central role in regulating the inflammatory process of the immune response and are identified based on the bone destruction that characterises the destructive phase of the disease [86,87].In particular, IL-1 and TNF are directly involved in osteoclastic resorption [88] by inhibiting osteoblast activity and promoting the release of CSF-1, also known as macrophage colony-stimulating factor [89].However, a secondary group of cytokines (such as IL-10) have antagonistic and periodontal protective effects [90].TNF is also involved in the pathogenesis of periodontitis.In fact, high levels of this cytokine upregulate the expression of RANKL in osteoblasts, T cells and gingival epithelial cells; therefore, it has been hypothesised that it may be associated with the early stage of periodontitis by altering the oral mucosal barrier [91].These inflammatory factors have also been found in people with depression.In summary, known pro-inflammatory cytokines of the IL-1, IL-6 and TNF families are secreted by periodontal cells and host immune cells after pathological stimulation, which activate and recruit specific immune cell subsets that cause direct tissue damage.Thus, T cells and B cells differentiate into mature T cells or plasma cells under the influence of specific cytokines and further activate or promote other effector cells, such as osteoclasts and neutrophils, which exert pro-inflammatory or anti-inflammatory effects [86][87][88][89]92].
In addition to biological factors, there are virological aspects in common between individuals with periodontitis and depression: Fusobacterium nucleatum has been identified in the brain tissue of animals with induced periodontitis, suggesting that this may be associated with HPA dysregulation and elevated corticosterone levels [34].Porphyromonas gingivalis, a major pathogen of periodontitis, inoculated into preclinical models every other day for 4 weeks, induced depression-like behaviours [93].This is followed by changes in the levels of neurotrophic receptors (in rats with both periodontitis and depression) [34].Also, the presence of stress hormones catecholamine, dopamine and cortisol increased proliferation and growth of Tannerella forsythia and Fusobacterium nucleatum [94].Therefore, stress-related adrenal hormones, such as catecholamines, can modulate the growth of some bacterial species, including Eikenella corrodens, Tannerella forsythia and Fusobacterium nucleatum [94,95], and drive the transition towards dysbiosis [32], a key element in the pathogenesis of periodontal disease [3].
Moreover, there are certain negative habits common to both diseases.Poor oral hygiene, smoking, alcohol consumption and poor or unregulated nutrition remain influential factors in both cases.
The articles analysed in the following review included 17 in vivo studies, which complied with the inclusion criteria, to understand the effects of antidepressant drugs on the periodontium in clinical and preclinical models.
Fluoxetine (an SSRIs) reduced periodontal progression [77], alveolar bone loss and inflammatory responses [79] in rats with induced periodontitis.Furthermore, it appears to influence periodontal genesis in mice without any clinically relevant effects by decreasing the number of periodontal cells [11].The beneficial effects of fluoxetine could be explained by its ability to reduce pathological inflammatory response and gene transcription when administered in an animal model [60,83].Intake of tianeptine, imipramine and desipramine is associated with a reduction in the level of alveolar bone loss and periodontal inflammation in mice.These molecules appear to exhibit immunomodulatory effects and can modulate bone remodelling and key inflammatory mediators [72,74,81,82].Desipramine (belonging to a tricyclic antidepressant) also appears to attenuate alveolar bone loss and modulate gene expression in mice [72].
In light of the results that emerged on animal models, although fluoxetine, imipramine, tianeptine, desvenlafaxine and desipramine appear to have anti-inflammatory and immunomodulatory properties, it is not possible to state with certainty the mechanism of action with which these drugs intervene at the periodontal level [71][72][73]81,82].
The results of studies performed on clinical models are contradictory.The recent study by Hakam et al. analysed the records of 582 patients divided into those with and without periodontitis [66].The periodontal parameters of patients taking different classes of antidepressants were compared with those of non-users.Subjects taking antidepressants (especially SSRIs such as fluoxetine or mixed classes) had statistically higher rates of alveolar bone loss and clinical attachment loss than periodontal patients not taking these drugs.Therefore, there are conflicting opinions on the effect of antidepressants on periodontal health: indeed, studies have shown improvements in periodontal and immunological indices with desvenlafaxine and fluoxetine treatment in patients with periodontitis and depression, while others have highlighted how the use of some antidepressants in the presence of periodontitis and depression limits periodontal loss and influences periodontal epidemiological indices [75], such as bleeding on probing and alveolar bone loss [78].
The antidepressant that appears to be more damaging to the periodontium is venlafaxine, which worsens PPD, CAL, GI and DI [67,68] and exacerbates bone loss due to synaptic inhibition of serotonin uptake, which has negative effects on the skeleton [76].
The contrasting results may be due to the different categories of antidepressants used in the studies included in this review: probably the negative or positive effects are linked precisely to the category of the drug and its application.
This review, which would seem to show that there is no effect on periodontal health in patients taking antidepressants (category), shows a strong risk in the studies-animal or human studies, different sample numbers, different antidepressants used and different dosages, different epidemiological indices analysed-these data could confuse the results emerging from this review, but also explain the reason for their diversity.
For future studies, it would be useful to use a uniform sample, with the same degree of periodontitis (even if induced), to which is administered the same type and dosage of antidepressant.In addition, it is possible to make a comparison with an untreated control group or with other groups of patients treated with other antidepressants, in an attempt to highlight the side effects that may arise.

Conclusions
Depressive disorders and periodontal disease have been reported to share distinct behavioural, inflammatory and bacterial translocation mechanisms.In particular, the pharmacology of depressive disorders and their association with the course of periodontal disease have been analysed in clinical and preclinical models.
Our analysis suggests that in the presence of comorbidity between periodontitis and depression, pharmacological treatment with SNRIs, SSRIs and mixed antidepressants is associated with an improvement in periodontal parameters (such as probing pocket depth, bleeding on probing, clinical attachment loss and bone loss), with the exception of venlafaxine (with worsening of periodontal indices, including bone loss).Therefore, it is not possible to provide a clear idea of the effect of antidepressants on periodontal health, which depends on their type and dosage.
Healthcare professionals (especially oral and mental health professionals) should assess the adherence to medication in patients with a history of periodontitis and depression.
Pharmacological treatment may modulate and reduce the inflammatory burden in patients diagnosed with both periodontitis and depression.Further studies are needed to analyse the cause-and-effect mechanisms underlying the depression-periodontitis associations and to investigate the anti-inflammatory and immunomodulatory effects of different antidepressants on the periodontium, using a uniform sample of patients with periodontal disease and the same class of antidepressant.These effects have not been well studied.
cluded f blinding, randomisation, allocation concealment, outcome data g were carried out to assess the bias risk of this review.According into consideration, a green symbol was assigned where the plete and accurate; a yellow symbol was allocated where ing; and a red symbol was assigned where the information did not .This review has low risk of bias.risk of bias in the main articles examined.rticles [66-68,70-83].be sensitive to fluoxetine, and its interference in reducing periodontal cells depends on exposure time during lactation Tianeptine Tianeptine inhibits bone loss Tianeptine Tianeptine inhibits bone loss Fluoxetine, Tianeptine and Venlafaxine Only Venlafaxine study was not to able to find any significant alveolar bone loss reduction, while others showed positive effects breviations.PPD: Probing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; P: Bleeding on probing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular eding index.
be sensitive to fluoxetine, and its interference in reducing periodontal cells depends on exposure time during lactation Tianeptine Tianeptine inhibits bone loss Tianeptine Tianeptine inhibits bone loss Tianeptine and Venlafaxine Only Venlafaxine study was not to able to find any significant alveolar bone loss reduction, while others showed positive effects bing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; ing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular cluded f blinding, randomisation, allocation concealment, outcome data g were carried out to assess the bias risk of this review.According into consideration, a green symbol was assigned where the plete and accurate; a yellow symbol was allocated where ing; and a red symbol was assigned where the information did not .This review has low risk of bias.risk of bias in the main articles examined.rticles [66-68,70-83].be sensitive to fluoxetine, and its interference in reducing periodontal cells depends on exposure time during lactation Tianeptine Tianeptine inhibits bone loss Tianeptine Tianeptine inhibits bone loss Fluoxetine, Tianeptine and Venlafaxine Only Venlafaxine study was not to able to find any significant alveolar bone loss reduction, while others showed positive effects breviations.PPD: Probing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; P: Bleeding on probing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular eding index.
; CAL: Clinical attachment loss; AL: Attachment loss; ing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular cluded f blinding, randomisation, allocation concealment, outcome data g were carried out to assess the bias risk of this review.According into consideration, a green symbol was assigned where the plete and accurate; a yellow symbol was allocated where ing; and a red symbol was assigned where the information did not .This review has low risk of bias.risk of bias in the main articles examined.rticles [66-68,70-83].and Venlafaxine to find any significant alveolar bone loss reduction, while others showed positive effects breviations.PPD: Probing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; P: Bleeding on probing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular eding index.
was not to able to find any significant alveolar bone loss reduction, while others showed positive effects bing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; ing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular cluded f blinding, randomisation, allocation concealment, outcome data g were carried out to assess the bias risk of this review.According into consideration, a green symbol was assigned where the plete and accurate; a yellow symbol was allocated where ing; and a red symbol was assigned where the information did not .This review has low risk of bias.risk of bias in the main articles examined.rticles [66-68,70-83].and Venlafaxine Only Venlafaxine study was not to able to find any significant alveolar bone loss reduction, while others showed positive effects breviations.PPD: Probing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; P: Bleeding on probing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular eding index.
was not to able to find any significant alveolar bone loss reduction, while others showed positive effects bing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; ing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular cluded f blinding, randomisation, allocation concealment, outcome data g were carried out to assess the bias risk of this review.According into consideration, a green symbol was assigned where the plete and accurate; a yellow symbol was allocated where ing; and a red symbol was assigned where the information did not .This review has low risk of bias.risk of bias in the main articles examined.rticles [66-68,70-83].and Venlafaxine Only Venlafaxine study was not to able to find any significant alveolar bone loss reduction, while others showed positive effects breviations.PPD: Probing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; P: Bleeding on probing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular eding index.

Fluoxetine
was not to able to find any significant alveolar bone loss reduction, while others showed positive effects bing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; ing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular cluded f blinding, randomisation, allocation concealment, outcome data g were carried out to assess the bias risk of this review.According into consideration, a green symbol was assigned where the plete and accurate; a yellow symbol was allocated where ing; and a red symbol was assigned where the information did not .This review has low risk of bias.risk of bias in the main articles examined.rticles [66-68,70-83].and Venlafaxine Only Venlafaxine study was not to able to find any significant alveolar bone loss reduction, while others showed positive effects breviations.PPD: Probing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; P: Bleeding on probing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular eding index.

Table 2 .
Antidepressants and their effects on the periodontium.

Sequence Generated Allocation Concealment Blinding Incomplete Outcome Data Registration Outcome Data
Abbreviations.PPD: Probing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; BOP: Bleeding on probing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular bleeding index.

Sequence Generated Allocation Concealment Blinding Incomplete Outcome Data Registration Outcome Data
Abbreviations.PPD: Probing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; BOP: Bleeding on probing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular bleeding index.

Sequence Generated Allocation Concealment Blinding Incomplete Outcome Data Registration Outcome Data
Abbreviations.PPD: Probing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; BOP: Bleeding on probing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular bleeding index.

Sequence Generated Allocation Concealment Blinding Incomplete Outcome Data Registration Outcome Data
Abbreviations.PPD: Probing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; BOP: Bleeding on probing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular bleeding index.

Sequence Generated Allocation Concealment Blinding Incomplete Outcome Data Registration Outcome Data
Abbreviations.PPD: Probing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; BOP: Bleeding on probing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular bleeding index.

Adequate Sequence Generated Allocation Concealment Blinding Incomplete Outcome Data Registration Outcome Data
Abbreviations.PPD: Probing pocket depth; CAL: Clinical attachment loss; AL: Atta BOP: Bleeding on probing; GI: Gingival index; BL: Bone level; PI: Plaque index; S bleeding index.
Muniz et al., 2018 [83]Fluoxetine, Tianeptine and Venlafaxine Only Venlafaxine study was not to able to find any significant alveolar bone loss reduction, while others showed positive effectsAbbreviations. PPD: Probing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; BOP: Bleeding on probing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular bleeding index.
Periodontal tissue may be sensitive to fluoxetine, and its interference in reducing periodontal cells depends on exposure time during lactation ivik et al., 2006 [81] Tianeptine Tianeptine inhibits bone loss ivik et al., 2006 [82] Tianeptine Tianeptine inhibits bone loss niz et al., 2018 [83] Fluoxetine, Tianeptine and Venlafaxine Only Venlafaxine study was not to able to find any significant alveolar bone loss reduction, while others showed positive effects Abbreviations.PPD: Probing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; BOP: Bleeding on probing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular bleeding index.
Periodontal tissue may be sensitive to fluoxetine, and its interference in reducing periodontal cells depends on exposure time during lactation Breivik et al., 2006 [81] Tianeptine Tianeptine inhibits bone loss Breivik et al., 2006 [82] Tianeptine Tianeptine inhibits bone loss Muniz et al., 2018 [83] Fluoxetine, Tianeptine and Venlafaxine Only Venlafaxine study was not to able to find any significant alveolar bone loss reduction, while others showed positive effects Abbreviations.PPD: Probing pocket depth; CAL: Clinical attachment loss; AL: Attachment loss; BOP: Bleeding on probing; GI: Gingival index; BL: Bone level; PI: Plaque index; SBI: Sulcular bleeding index.